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United States Patent | 5,686,565 |
Kyle ,   et al. | November 11, 1997 |
Pseudopeptide compounds based on a modified bradykinin sequence are potent bradykinin receptor antagonist. All or a portion of the amino acids at positions 2 through 5 of the bradykinin sequence are replaced by 2-pyrrolidinyl and/or amino-alkanoic acid or related olefinic derivatives to reduce the peptidic nature of the compounds. The analogs produced are useful in treating conditions and diseases of a mammal and human in which an excess of bradykinin or related kinins are produced or injected such as by insect bites.
Inventors: | Kyle; Donald James (Abingdon, MD); Mavunkel; Babu Joseph (Timonium, MD) |
Assignee: | Scios Inc. (Mountain View, CA) |
Appl. No.: | 281904 |
Filed: | July 28, 1994 |
Current U.S. Class: | 530/328 |
Intern'l Class: | A61K 038/08 |
Field of Search: | 514/15-17 530/328,329,314 |
4242329 | Dec., 1980 | Claeson et al. | 424/177. |
4483850 | Nov., 1984 | Patchett et al. | 424/177. |
4693993 | Sep., 1987 | Stewart et al. | 514/14. |
4801613 | Jan., 1989 | Stewart et al. | 514/14. |
4822984 | Apr., 1989 | Geiger et al. | 548/252. |
4923963 | May., 1990 | Stewart et al. | 530/314. |
Foreign Patent Documents | |||
0334685 | Sep., 1989 | EP. | |
0 370 453 | May., 1990 | EP. | |
0 413 277 | Feb., 1991 | EP. | |
92/18155 | Oct., 1992 | WO. | |
92/18156 | Oct., 1992 | WO. | |
WO 94/08607 | Apr., 1994 | WO. |
Karanewsky et al., "(Phosphinyloxy)acyl amino acids inhibitors of angiotensin converting enzyme. 2. Terminal amino acid analogues of (S)-1-›6-amino-2››hydroxy(4-phenylbutyl)phosphinyl!oxy!-1-oxohexyl!-L-prol ine" J. Med. Chem. (1990) 33(5):1459-1469. Smith et al., "Synthesis and pharmacological activity of angiotensin converting enzyme inhibitors: N-(mercaptoacyl)-4-substituted-(S)-prolines" J. Med. Chem. (1988) 31(4):875-885. Krapcho et al., "Angiotensin converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines" J. Med. Chem. (1988) 31(6):1148-1160. Hock et al., "Hoe 140 a new potent and long acting bradykinin antagonist: in vitro studies" Br. J. Pharmacol. (1991) 102:769-744. Wirth et al., "Hoe 140 a new potent and long acting bradykinin antagonist: in vivo studies" Br. J. Pharmacol. (1991) 102:774-777. Pongracic et al., "A competitive kinin receptor antagonist, ›DArg.sup.0, Hyp.sup.3, DPhe.sup.7 !-bradykinin, does not affect the response to nasal provocation with bradykinin" Br. J. Pharmacol. (1991) 31:287-294. Higgins et al., "A study of the efficacy of the bradykinin antagonist NPC567 in rhinovirus infections in human volunteers" Chemical Abstracts (1991) 114:220805d. Soler et al., "A bradykinin antagonist amodifies ntigen-induced airway hyper-responsiveness and airway inflammation in allergic sheep" Am. Rev. Respir. Dis. (1989) A327. Stewart, John M., "Hydroxyproline analogs of bradykinin" J. Med. Chem. (1974) 17(5):537-539. Stewart, John M., "Chemistry and biologic activity of peptides related to bradykinin" Handbook of Experimental Pharmacol. (1979) vol. XXV Supp, Springer-Verlag Berlin Heidelberg NY. Vavrek et al., "Smooth muscle selectivity in bradykinin analogs with multiple D-amino acid substitutions", Dept. of Biochem., University of Colorado School of Medicine, Denver, Colorado. Rifo et al., "Bradykinin receptor antagonists used to characterize the heterogeneity of bradykinin-induced responses in rat vas deferens" Eur. J. Pharmacol. (1987) 142:305-312. Zeitlin et al., "Mobilization of tissue kallikrein in inflammatory disease of the colon" Wolfson Labs. Gastrointestinal Unit, West General Hospital and Dept. of Clinical Surgery, Univ. of Edinburgh (1972) pp. 113-138. Suzuki et al., "Synthesis of every kind of peptide fragments of bradykinin" Chem. Pharm. Bull. (1969) 17:1671-1678. Dray et al. "Bradykinin and inflammatory pain" TINS (1993) 16(3):99-104. Perkins et al., "Antinociceptive activity of the bradykinin B.sub.1 and B.sub.2 receptor antagonists, des-Arg.sup.9, ›Leu.sup.8 !-BK and HOE 140, in two models of persistent hyperalgesia in the rat" Pain (1993) 53:191-197. Zabrocki et al., "Conformational Mimicry. 3. Synthesis and incorporation of 1,5-disubstituted tetrazole dipeptide analogues into peptides with preservation of chiral integrity: bradykinin" J. Org. Chem. (1992) 57(1):202-209. Hodges et al. (eds.) Peptides, Chemistry, Structure and Biology: Proceedings of the 13th American Peptide Symposium Jun. 20-25, 1993 (ESCOM: Leiden, 1994), pp. 381-383. Kyle et al., "A proposed model of bradykinin bound to the rat B.sub.2 receptor and its utility for drug design" J. Med. Chem. (1994) 37(9):1347-1354. Abstracts of Papers, Part 1: 208th American Chemical Society National Meeting Aug. 21-25, 1994 190. Kyle et al., "NMR and computational evidence that high-affinity bradykinin receptor antagonists adopt C-terminal .beta.-turns" J. Med. Chem. (1993) 36(10):1450-1460. Hodges et al. (eds.) Peptides, Chemistry, Structure and Biology: Proceedings of the 13th American Peptide Symposium Jun. 20-25, 1993 (ESCOM: Leiden, 1994), pp. 449-451. |
TABLE I ______________________________________ ##STR1## ______________________________________
TABLE I __________________________________________________________________________ K.sub.i (nM) NPC No. Human Compound 17731 Guinea __________________________________________________________________________ Pig 18424 ##STR15## 15 174 18465 ##STR16## 2123 18466 ##STR17## 1896 18467 ##STR18## 400 18484 ##STR19## 358 18608 ##STR20## 21 ##STR21## 1267 .+-. 173 ##STR22## 28 __________________________________________________________________________